Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model
Ashok D. Prabakaran, … , Brian N. Finck, Mattia Quattrocelli
Ashok D. Prabakaran, … , Brian N. Finck, Mattia Quattrocelli
Published May 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e177427. https://doi.org/10.1172/JCI177427.
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Research Article Aging Muscle biology Article has an altmetric score of 18

Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model

Abstract

Sarcopenia burdens the older population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are lacking. The glucocorticoid prednisone remodels muscle metabolism on the basis of frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone administration rescued muscle quality in aged 24-month-old mice to a level comparable to that seen in young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing peroxisome proliferator–activated receptor γ coactivator 1 α (PGC1α) and its cofactor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed myocyte-specific Lipin1 as a nonredundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes for the coordinated rescue of energy and mass in sarcopenia.

Authors

Ashok D. Prabakaran, Kevin McFarland, Karen Miz, Hima Bindu Durumutla, Kevin Piczer, Fadoua El Abdellaoui Soussi, Hannah Latimer, Cole Werbrich, Hyun-Jy Chung, N. Scott Blair, Douglas P. Millay, Andrew J. Morris, Brendan Prideaux, Brian N. Finck, Mattia Quattrocelli

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Figure 5

Myocyte-specific Lipin1 controls energy-mass balance in muscle.

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Myocyte-specific Lipin1 controls energy-mass balance in muscle. (A) MyoA...
(A) MyoAAV-mediated overexpression in WT muscle 2 weeks after r.o. injection of 1012 vg/mouse (left). Combination of AAV and treatment in PGC1α-KO mice revealed an additive effect of the treatment on genetic rescue of mitochondrial abundance by Pgc1α isoform 1 and muscle mass by PGC1α isoform 4 (right) in tibialis anterior muscles. Together with our RNA-Seq/ChIP-Seq screening, the additive effect warranted investigation of Lipin1 as a treatment-driven cofactor to coax PGC1α regulation with energy-mass balance. (B) ANCOVA for VO2 in metabolic cages without specific exercise triggers showed increased VO2 independent from body mass in control (WT Lipin1) mice, but not after Lipin1 ablation (Lipin1-KO). (C) In the metabolic treadmill test, treatment increased VO2max as well as speed and work until exhaustion dependent on myocyte-specific Lipin1. (D and E) Lipin 1 was critical for treatment-driven effects on muscle force and fatigability and mitochondrial respiration. (F and G) Analogously to its cofactor PGC1α manipulation, Lipin1 ablation blunted or blocked treatment effects on muscle mass in 2 different locomotory muscles (tibialis, hind limbs; triceps, forelimbs). (H) KO of Lipin1 blocked the additive effect of treatment on top of the PGC1α isoform 1 and isoform 4 overexpression effect on mitochondrial abundance, tibialis anterior muscle mass, and grip strength. n = 3–5/group. Histograms and curves report the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; 2-way ANOVA with Šidák’s test.